Most vertebrate species are responsive to five basic tastes: sweet, bitter, umami, sour and salty, each of which provides unique information on the nutritional content and safety of ingested food. Each of the five taste qualities is detected by a distinct subset of taste receptor cells found in taste buds on the tongue and the palate epithelium. While great strides have been made in understanding the molecules and mechanisms that mediate bitter, sweet, and umami tastes, relatively little is known about the electrophysiological basis for sour taste. The cells that detect sour taste can be identified by expression of the TRP ion channel PKD2L1, which itself is not necessary for sour taste. In recent work, using a mouse in which yellow fluorescent protein (YFP) was driven by the promoter of Pkd2l1, we showed that sour taste cells have a previously uncharacterized proton conductance which is apically located and carries an inward current in response to extracellular acidification. This has led us to propose a model in which proton entry through the proton channel depolarizes the cells leading to action potentials and transmitter release. In addition, proton entry may cause cytosolic acidification, which could act on resting K+ channels to further depolarize the cells. This process may be subject to modulation at multiple steps, allowing the system to adapt to varying conditions and needs of the organism. The present proposal include three specific aims that take advantage of these newly generated transgenic mouse lines and recent results from transcriptome profiling to test this model and to further elucidate mechanisms of sour transduction. Taste is an essential way in which humans and other organisms regulate their ingestive behavior and the identification of mechanisms of taste signaling can therefore have a direct impact on human health and well-being.